1. Technical Field of the Invention
The present invention relates to novel C-glycoside derivatives, to a process for synthesizing these and to compositions comprised thereof.
The present invention also relates to the administration, in a physiologically acceptable medium, in a cosmetic composition or for the preparation of a pharmaceutical composition, of at least one C-glycoside derivative, the compound or the composition being suited to stimulate the synthesis of glycosaminoglycans containing a D-glucosamine and/or N-acetyl-D-glucosamine residue, advantageously hyaluronic acid, and/or proteoglycans, advantageously proteoglycans containing hyaluronic acid, by fibroblasts and/or keratinocytes.
This invention also relates to a cosmetic regime or regimen comprising administering to an individual in need of such treatment such a cosmetic composition.
2. Description of Background/Related/Prior Art
Human skin consists of two compartments, namely, a superficial compartment, the epidermis, and a deep compartment, the dermis.
Natural human epidermis is composed mainly of three types of cell: the keratinocytes, which form the vast majority, the melanocytes and the Langerhans cells. Each of these cell types contributes by virtue of its intrinsic functions, towards the essential role played in the body by the skin.
The dermis gives the epidermis a solid support. It is also the epidermis' nourishing factor. It consists mainly of fibroblasts and of an extracellular matrix. Leukocytes, mastocytes and tissue macrophages are also found in the dermis. It also consists of blood vessels and nerve fibers.
The extracellular matrix of the dermis, like that of all the connective tissues of the body, is composed of proteins belonging to several major families: collagens, matrix glycoproteins other than collagens (fibronectin, laminin), elastin and proteoglycans. Glycosaminoglycans in free form (i.e., not attached to a protein) are also found in the extracellular matrix of the dermis, like that of all the connective tissues of the body.
It is now well established that specific interactions exist between these various classes of proteins to give rise to a functional tissue.
Proteoglycans are complex macromolecules consisting of a branched central protein trunk, or protein network, to which are attached numerous polyoside side chains known as glycosaminoglycans.
Hereinbelow in the present patent application, proteoglycans will be denoted by the abbreviation PG and glycosaminoglycans by the abbreviation GAG.
GAGs have long been referred to by the term acidic mucopolysaccharides on account of their high water-retaining capacity, their carbohydrate nature and their acidic nature derived from the numerous negative charges thereon.
Thus, the polarity of GAGs implicitly makes them participate in certain biological functions, for instance the moisturization of tissues, the fixing of cations or the barrier role of ionic filtration.
PGs and GAGs are synthesized by various cells in the dermis and the epidermis: fibroblasts, keratinocytes and melanocytes.
The fibroblasts mainly synthesize collagens, matrix glycoproteins other than collagens (fibronectin, larinin), proteoglycans and elastin. The keratinocytes mainly synthesize sulfated GAGs and hyaluronic acid, while the melanocytes apparently do not produce any hyaluronic acid.
When they are incorporated in a PG, GAGs are linear chains composed of a repetition of a base diholoside always containing a hexosamine (glucosamine or galactosamine) and another saccharide (glucuronic acid, iduronic acid or galactose). The glucosamine is either N-sulfated or N-acetylated. On the other hand, the galactosamine is always N-acetylated. In addition, there may be sulfates O-bonded to the hexosamine, uronic acid and galactose.
The strong anionic nature of GAGs is explained by the presence of carboxylate groups in the hexuronic acids (glucuronic acid and iduronic acid) and of O- and N-bonded sulfate groups.
The main GAGs are hyaluronic acid or hyaluronan (HA), heparan sulfate (HS), heparin (HP), chondroitin, chondroitin sulfate (CS), chondroitin 4-sulfate or chondroitin sulfate A (CSA), chondroitin 6-sulfate or chondroitin sulfate C (CSC), dermatan sulfate or chondroitin sulfate B (CSB) and keratan sulfate (KS), which differs from the other glycosaminoglycans by the presence of galactose in the place of uronic acid.
When they are combined with a protein in the form of PG, the GAGs are linked via anchoring structures to the various polypeptide chains, named the “core” protein or carrier protein, and thus form PG molecules.
GAGs may also exist in the extracellular matrix in free form, i.e., not bound to a matrix protein: this is especially the case for hyaluronic acid.
During the synthesis of PGs, the GAGs are polymerized from these anchoring structures.
The synthesis of GAGs requires the coordinated and concerted action of very specific enzymes (transferases, epimerases and sulfotransferases) that are adjacent in the membrane of the endoplasmic reticulum and of the golgi bodies. Next, a host of biochemical reactions (N-deacetylation, N- and O-sulfation, and epimerization) modify the two constituent saccharides of the base unit, heterogeneously along the chain. For example, from one heparan sulfate chain to another, the glucuronic acid/iduronic acid ratio, the nature, number and position of the O-sulfations, and the N-sulfate/O-sulfate ratio may vary, which essentially offers immense structural diversity.
In general, the biological roles of PGs are highly diversified, ranging from a passive mechanical support function (for example serglycines) or an ionic barrier role in molecular filtration (for example perlecane and bamacane of the glomerular basal membrane), to more specific effects in cell adhesion, spreading, proliferation and differentiation or morphogenesis, or to highly specific effects of PG-protein interactions, such as the beta-glycan receptor function or the interaction of decorin with collagen.
One of the roles of dermal connective tissue is to protect the body against external attack by simultaneously forming an informative interface.
To do this, the dermis has high mechanical strength while maintaining, however, great flexibility.
Its strength is ensured by the dense network of collagen fibers, but it is the PGs and the hyaluronic acid which, by ensuring the moisturization, distribution and suppleness of the fibers, make the difference between the skin and, for example, leather.
The PGs constitute 0.5% to 2% of the dry weight of the dermis, collagen alone representing up to 80% of this weight.
The concentration and distribution in human skin of GAGs and PGs vary with age.
Hyaluronic acid or hyaluronan (HA) is the main GAG of the dermis, the latter containing half the HA of the body.
The synthesis of HA is performed especially by the fibroblasts, close to the inner face of the plasma membrane. It is performed continuously. This gigantic polysaccharide (several million daltons) has a very high intrinsic viscosity, ensuring the moisturization and assembly of the various components of the connective tissue by forming supramolecular complexes.
Dermatan sulfate (DS), which was first isolated from the dermis, is also widely abundant in the skin. It constitutes 40% to 50% of the dermal GAGs.
In parallel with the mechanisms contributing to the development of these specialized extracellular matrices, continuous remodeling processes exist, the regulation of which depends on the balance between the synthesis and degradation of the protein components of the matrix.
Several families of matrix proteases are now described, as are the factors involved in their activation-inactivation.
In the course of chronological and/or actinic aging, the dermis and the epidermis undergo several changes and degradations which are reflected, with age, by flaccidness and a loss of suppleness of the skin.
Among the components degraded (especially collagen and elastin), the PGs and GAGs are also adversely affected. Specifically, over the course of aging, the fibroblasts and keratinocytes produce less and less PGs and GAGs and their synthesis is imperfect. This results in considerable disorganization: the deposition of GAGs on the protein skeleton forming the PG is abnormal, the consequence of this is a reduced avidity for water of these PGs thus a reduction in the moisturization and tonicity of tissues.
Restoring a normal production of PGs and GAGs by fibroblasts and keratinocytes contributes partially towards compensating for the loss of moisturization of the skin.
The degradation of these matrices thus contributes towards the phenomenon of dryness and of loss of suppleness of the skin.
The importance of having available active agents whose effects are directed towards maintaining the level of PGs and GAGs in the skin and thus of maintaining, inter alia, good moisturization and good suppleness of the skin will thus be appreciated.